The present invention relates to a carboxylic acid derivative and a peroxisome proliferator activated receptor regulator containing carboxylic acid derivative as active ingredient.
More particularly, the present invention relates to a peroxisome proliferator activated regulator containing a compound of formula (I) 
(wherein all symbols are as hereinafter described), a non-toxic salt thereof and a hydrate thereof as active ingredient, a novel carboxylic acid derivative of formula (I), a non-toxic salt thereof, a hydrate thereof and a process for the preparation thereof.
Recently in the study of transcription factors concerned with genes expression in adipocytes differentiation, peroxisome proliferator activated receptor (abbreviated as PPAR hereinafter) has been focused. cDNAs of PPAR were cloned from various kinds of animals, and plural isoform genes were found, particularly in mammals three types of isoforms (xcex1, xcex4, xcex3) are known (see J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Gene Expression,. 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol. Endocrinology., 6, 1634 (1992)). PPAR xcex3 isoform is predominantly expressed in adipose tissues, immune cells, adrenal gland, spleen, small intestine. PPAR xcex1 isoform is mainly expressed in adipose tissue, liver, retina, and xcex4 isoform shows the expression with no tissue specificity, which is widely expressed (see Endocrinology., 137, 354 (1996)).
On the other hand, the following thiazolidine derivatives are known as agents for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and are hypoglycemic agents which are used for the improvement of hyperglycemia in the patients suffering from diabetes. They are also effective for the improvement of hyperinsulinemia, glucose tolerance and decrease of serum lipid and therefore they are thought to be considerably hopeful as agents for the treatment of insulin resistance. 
One of the target proteins in the cells of these thiazolidine derivatives is exactly PPAR xcex3 and it is resolved that they enhance the transcription activity of PPAR xcex3 (see Endocrinology., 137, 4189 (1996); Cell., 83, 803 (1995); Cell., 83, 813 (1995); J. Biol. Chem., 270, 12953 (1995)). Therefore, a PPAR activator (agonist) which enhances its transcription activity is thought to be hopeful as a hypoglycemic agent and/or a hypolipidemic agent. Furthermore, since a PPAR xcex3 agonist is known to promote the expression of PPAR xcex3 protein itself (Genes and Development., 10, 974 (1996)), an agent which increases the expression of PPAR xcex3 protein itself as well as PPAR xcex3 activating agent is also clinically useful.
Among all of nuclear receptors, PPAR xcex3 is related to adipocytes differentiation (see J. Biol. Chem., 272, 5637 (1997) and Cell., 83, 803 (1995)). It is known that thiazolidine derivatives which activate this receptor promote adipocytes differentiation. Recently it was reported that thiazolidine derivatives increase fat mass and cause man to gain weight and to become obese (see Lancet., 349, 952 (1997)). Therefore, it is also thought that antagonists which inhibit PPAR xcex3 activity and agents that decrease the expression of PPAR xcex3 protein itself are also clinically applicable. On the other hand, a compound that phosphorylates PPAR xcex3 protein and decreases its activity is reported (Science., 274, 2100 (1996)). This implies that an agent which does not bind on PPAR xcex3 protein as a ligand, but inhibits its activity is also clinically applicable.
From these, PPAR xcex3 activators (agonists) and PPAR xcex3 regulators for its expression that can increase the expression of the protein itself are expected to be useful as hypoglycemic agents, hypolipidemic agents, preventives and/or remedies for diseases associated with metabolic disorders (diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipidemia, atherosclerosis, hypertension, circulatory diseases, overeating, etc.
On the other hand, antagonists that inhibit the transcription activity of PPAR xcex3 or PPAR xcex3 regulators that inhibit the expression of the protein itself are expected to be useful as hypoglycemic agents, preventives and/or remedies for diseases associated with metabolic disorders (diabetes, obesity, syndrome X, etc.), hyperlipidemia, atherosclerosis, hypertension, overeating, etc.
The following fibrate compound (e.g. chlofibrate) is known as a hypolipidemic agent. 
It is also resolved that one of the target proteins in the cells of fibrate compounds is PPAR xcex1 (See Nature., 347, 645 (1990); J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Biochemistry., 32, 5598 (1993)). From these facts, PPAR xcex1 regulators, which can be activated by fibrate compounds are thought to have a hypolipidemic effect, and so they are expected to be useful as preventives and/or remedies for hyperlipidemia etc.
Besides, it was recently reported that biological activation of PPAR xcex1 linked anti-obese effect in the specification of WO 9736579. It was reported that the elevation of high density lipoprotein (HDL) cholesterol and the reduction of low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol and triglyceride were induced by PPAR xcex1 activation (J. Lipid Res., 39, 17 (1998)). It was also reported that improvement of fatty acid composition in the blood, hypertension and insulin resistance by the treatment of bezafibrate (one of fibtrate compounds) (Diabetes., 46, 348 (1997)). Therefore, agonists that activate PPAR xcex1 and PPAR xcex1 regulators that promote expression of PPAR xcex1 protein itself are useful as hypolipidemic agents and remedies for hyperlipidemia , and are expected to have HDL cholesterol-elevating effect, LDL cholesterol and/or VLDL cholesterol-lowering effect, inhibition on the progress of atherosclerosis and anti-obese effect. Therefore, they are thought to be hopeful agents for the treatment and/or prevention of diabetes as hypoglycemic agents, for the improvement of hypertension, for the relief from risk factor of syndrome X and for the prevention of occurrence of coronary heart diseases.
On the other hand, few reports are found on ligands that activate PPAR xcex4 significantly or on biological activities associated with PPAR xcex4.
PPAR xcex4 is sometimes called PPAR xcex2, or it is also called NUC1 in human. So far it was shown that in the specification of WO 9601430 hNUC1B (PPAR subtype whose structure is different from that of human NUC1 in one amino acid) inhibited the transcription activities of human PPAR xcex1 and thyroid hormone receptor. Recently in the specification of WO 9728149, it was reported that compounds bound to PPAR xcex4 protein with high affinity activated PPAR xcex4 significantly (i.e. agonists) and they had HDL (high density lipoprotein) cholesterol-elevating activity. Therefore, agonists :that activate PPAR xcex4 are expected to have HDL cholesterol-elevating effect, and so they are expected to be useful for the inhibition on the progress of atherosclerosis and its treatment, as hypolipidemic agents and/or hypoglycemic agents, for the treatment of hyperlipidemia, as hypoglycemic agents, for the treatment of diabetes, for the relief from risk factor of syndrome X, and for the prevention of occurrence of coronary heart diseases.
The following PPAR regulators have been reported.
(1) For example, in the specification of WO 9728115, it is described that a compound of formula (A) 
(wherein R1A is selected from hydrogen, C3xcx9c10 cycloalkyl, etc., R2A is selected from hydrogen, C5xcx9c10 aryl, C5xcx9c10 heteroaryl, etc., R4A is selected from R2A etc., (ZAxe2x80x94WAxe2x80x94) is ZAxe2x80x94CR6AR7A or ZAxe2x80x94CR6AR7Axe2x80x94R8Axe2x80x94, etc., R8A is selected from CR6AR7A, O, S(O)pA, etc., R6A and R7A are each independently, selected from hydrogen, C1xcx9c6 alkyl, etc., X1A and X2A are each independently, hydrogen, C1xcx9c15 alkyl, halogen, etc., YA is selected from S(O)pA, xe2x80x94Oxe2x80x94, etc., Y1A is selected from O, C, etc., ZA is selected from CO2R3A etc., tA and vA are each independently 0 or 1, tA+vA is 1, QA is saturated or unsaturated 2xcx9c4 straight-chained hydrocarbon, pA is 0xcx9c2, R3A is hydroxy, C1xcx9c15 alkoxy, etc.) or a pharmaceutically acceptable salt thereof is a PPAR xcex4 modulator (necessary part is extracted in the explanation of the group). In the specifications of WO 9727857 and WO 9728137, it is described that analogous compounds therewith are also PPAR xcex4 modulators.
(2) In the specification of WO 9731907, it is described that a compound of formula (B) 
(wherein AB is phenyl, said phenyl may be substituted by one or more of halogen, C1xcx9c6 alkyl, C1xcx9c3 alkoxy, C1xcx9c3 fluoroalkoxy, nitrile or xe2x80x94NR7BR8B (R7B and R8B are each independently hydrogen or C1xcx9c3 alkyl);
BB is 5 or 6-membered hetero ringxe2x80x94C1xcx9c6 alkylene-, said hetero ring may be substituted by C1xcx9c3 alkyl;
AlkB is C1xcx9c3 alkylene;
R1B is hydrogen or C1xcx9c3 alkyl;
ZB is selected from xe2x80x94(C1xcx9c3 alkylene)phenyl or xe2x80x94NR3BR4B) or a pharmaceutically acceptable salt thereof has PPAR xcex3 agonist activity (necessary part is extracted in the explanation of the group).
(3) In the specification of JP Kokai Hei 9-323982, it is described that a propionic acid derivative of formula (C) 
(wherein Rxe2x80x2C is an optionally substituted aromatic hydrocarbon, an optionally substituted cyclic aliphatic hydrocarbon, an optionally substituted hetero ring or an optionally substituted fused hetero ring and R5C is lower alkyl), R4C is hydrogen or lower alkyl, R6C is hydrogen or taken together with R9C to form a double bond, R7xe2x80x2C is hydrogen, hydroxy, carboxy, acyl, optionally substituted alkoxycarbonyl, optionally substituted lower alkyl, optionally substituted carbamoyl, optionally substituted aryloxycarbonyl, optionally substituted aralkyloxycarbonyl or a group represented by formula xe2x80x94YCxe2x80x94RC (wherein YC is xe2x80x94NHxe2x80x94 or oxygen, R8C is optionally substituted acyl, optionally substituted alkoxycarbonyl, aryloxycarbonyl or aralkyloxycarbonyl), R9C is hydrogen, optionally substituted lower alkyl or optionally substituted lower alkoxycarbonyl, R10C is hydroxy, optionally substituted amino, optionally substituted lower alkoxy, optionally substituted lower alkyl, optionally substituted aryloxy or optionally substituted aralkyloxy) or a pharmaceutical composition containing a pharmaceutically acceptable salt thereof has hypoglycemic effect and hypolipidemic effect. In the specifications of JP Kokai Hei 8-325264, JP Kokai Hei 8-325250, WO 9638415 and WO 9800137, it is described that analogous compounds therewith have hypoglycemic effect and hypolipidemic effect.
(4) In the specification of JP Kokai Hei 8-104688, it is described that a compound of formula (D) 
(wherein RD is an optionally substituted hydrocarbon residue or a hetero ring which may be bound through carbon chain(s), nD is 0 or 1, XD is CH or N, YD is a bivalent hydrocarbon residue. R1D and R2D are the same or different to represent hydrogen, halogen, optionally substituted hydroxyl or an optionally substituted hydrocarbon residue, and either of R1D or R2D may be taken attached to a part of YD to form a ring) or a salt thereof has hypoglycemic effect and hypolipidemic effect. In the specification of JP Kokai Sho 61-85372, it is described that analogous compounds therewith also have hypoglycemic effect and hypolipidemic effect.
(5) In the specification of JP Kokai Hei 1-143856, it is described that a compound of formula (E) 
(wherein XE is xe2x80x94CR4Exe2x95x90 or xe2x80x94Nxe2x95x90, YE is xe2x80x94CR4Exe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90CR4Exe2x80x94, xe2x80x94CR4Exe2x95x90CR4Exe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR4Exe2x80x94, ZE is xe2x80x94(CH2)nEOxe2x80x94, xe2x80x94(CH2)nESxe2x80x94, etc., R1E is xe2x80x94(CHR7E)nECOOR6E etc., nE is each independently 0xcx9c5, R2E is each hydrogen, lower alkyl, lower alkoxy, trifluoromethyl, nitro, cyano or halogen, etc., R3E is 
WE is a bond or xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR4Exe2x80x94, mE is 1xcx9c15, R4E is each independently hydrogen or lower alkyl, R7E is hydrogen or methyl) or a pharmaceutically acceptable salt thereof has an inhibitory activity against lipoxygenase and a competitive activity against leucotriene.
(6) In the specification of JP Kohyo Hei 8-504194, it is described that a compound of formula (F) 
(wherein xe2x80x9cAryl Fxe2x80x9d is a monocyclic 6-membered hetero ring system containing 0, 1, 2, 3 or 4 of N atom and having no substituents or substituted by R5F;
XF is a mono- or multi-cyclic aromatic or non-aromatic 4xcx9c10 membered ring system etc. containing 0, 1, 2, 3 or 4 of hetero atom selected from N, O and S and having no substituents or substituted by R1F, R2F, R3F or R4F,
R1F, R2F, R3F and R4F are independently selected from a group of hydrogen, C1xcx9c10 alkyl, C3xcx9c8 cycloalkyl, aryl C0xcx9c8 alkyl, amino C0xcx9c8 alkyl, C1xcx9c6 alkylamino C0xcx9c8 alkyl, C1xcx9c6 dialkylamino C0xcx9c8 alkyl, C1xcx9c4 alkoxy C0xcx9c6 alkyl, etc.;
YF is C0xcx9c8 alkyl, C0xcx9c8 alkyl-O-C0xcx9c8 alkyl, C0xcx9c8 alkyl-SOnFxe2x80x94C0xcx9c8 alkyl, etc., wherein nF is an integer of 0xcx9c2,
ZF and AF are independently selected from (CH2)mF, (CH2)mFO(CH2)nF, (CH2)mFSO2(CH2)nF, (CH2)mFS(CH2)nF, (CH2)mFSO(CH2)nF, etc., wherein mF and nF are integers independently selected from 0xcx9c6, with the proviso that when
AF is (CH2)mF, xe2x80x9cAryl Fxe2x80x9d which is attached to ZF and AF must contain at least 1 hetero atom;
R5F is hydrogen, C1xcx9c6 alkyl, C0xcx9c6 alkyloxy C0xcx9c6 alkyl, or halogen, etc., BF is 
wherein
R6F, R7F, R8F, R9F, R10F and R11F are independently selected from hydrogen, C1xcx9c8 alkyl, etc.,
R12F is selected from hydroxy, C1xcx9c8 alkyloxy, etc.) and a pharmaceutically acceptable salt have fibrinogen receptor antagonist activity (necessary part is extracted in the explanation of the group).
As a result of energetic investigations in order to find compounds which possess PPAR regulating activity, the present inventors have found that the purpose is accomplished by the compound of formula (I).
Part of the compounds of formula (I) is known by the said specifications of JP Kokai Hei 1-143856 and JP Kohyo Hei 8-504194. The effects of these compounds, that is to say, lipoxygenase inhibitory activity, leucotriene competitive activity and fibrinogen receptor antagonist activity are also known, but PPAR regulating effect of these compounds is not easily expected from these facts.
The other part of the compounds of formula (I) is novel which has never been known so far.
The present invention relates to
1) a peroxisome proliferator activated receptor regulator containing a carboxylic acid derivative of formula (I) 
(wherein
A1 is C1xcx9c4 alkylene or C2xcx9c4 alkenylene,
A2 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94,
A3 is CH or N,
n is 1xcx9c5,
R1 is
(i) hydrogen,
(ii) C1xcx9c8 alkyl,
(iii) halogen,
(iv) C1xcx9c4 alkoxy,
(v) nitro,
(vi) trihalomethyl,
(vii) trihalomethoxy,
(viii) trihalomethylthio,
(ix) cyano,
(x) C1xcx9c4 alkylthio,
(xi) NR5R6 (wherein R5 and R6 are each independently, hydrogen or C1xcx9c4 alkyl),
(xii) carbocyclic ring or
(xiii) hetero ring,
R2 is
(i) hydrogen,
(ii) C1xcx9c4 alkyl,
(iii) halogen or
(iv) trihalomethyl,
Cyc1 is 
Cyc2 is
(i) carbocyclic ring or
(ii) hetero ring,
R3 is
(i) hydrogen,
(ii) C1xcx9c8 alkyl,
(iii) halogen,
(iv) C1xcx9c4 alkoxy,
(v) nitro,
(vi) trihalomethyl,
(vii) trihalomethoxy,
(viii) trihalomethylthio,
(ix) cyano or
(x) C1xcx9c4 alkylthio,
R4 is 
(ii) 2,4-thiazolidindion-5-yl,
A4 is
(i) bond,
(ii) C1xcx9c4 alkylene,
(iii) xe2x80x94C1xcx9c4 alkylene-Oxe2x80x94 or
(iv) xe2x80x94C1xcx9c4 alkylene-Sxe2x80x94,
R7, R8 and R9 are each independently hydrogen or C1xcx9c4 alkyl, with the proviso that
(1) R4 is attached to 2- or 3-position and
(2) when R4 is attached to 3-position, A4 is bond or methylene, A3 is CH and Cyc1 is benzene, then A1 is methylene, ethylene or vinylene.), its non-toxic salt or hydrate thereof as active ingredient,
2) a carboxylic acid derivative of formula (I) 
(wherein
A1 is C1xcx9c4 alkylene or C2xcx9c4 alkenylene,
A2 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94,
A3 is CH or N,
n is 1xcx9c5,
R1 is
(i) hydrogen,
(ii) C1xcx9c8 alkyl,
(iii) halogen,
(iv) C1xcx9c4 alkoxy,
(v) nitro,
(vi) trihalomethyl,
(vii) trihalomethoxy,
(viii) trihalomethylthio,
(ix) cyano,
(x) C1xcx9c4 alkylthio,
(xi) NR5R6 (wherein R5 and R6 are each independently hydrogen or C1xcx9c4 alkyl),
(xii) carbocyclic ring or
(xiii) hetero ring,
R2 is
(i) hydrogen,
(ii) C1xcx9c4 alkyl,
(iii) halogen or
(iv) trihalomethyl,
Cyc1 is 
Cyc2 is
(i) a carbocyclic ring or
(ii) a hetero ring,
R3 is
(i) hydrogen,
(ii) C1xcx9c8 alkyl,
(iii) halogen,
(iv) C1xcx9c4 alkoxy,
(v) nitro,
(vi) trihalomethyl,
(vii) trihalomethoxy,
(viii) trihalomethylthio,
(ix) cyano or
(x) C1xcx9c4 alkylthio,
R4 is 
(ii) 2,4-thiazolidindion-5-yl,
A4 is
(i) bond,
(ii) C1xcx9c4 alkylene,
(iii) xe2x80x94C1xcx9c4 alkylene-Oxe2x80x94 or
(iv) xe2x80x94C1xcx9c4 alkylene-Sxe2x80x94,
R7, R8 and R9 are each independently hydrogen or C1xcx9c4 alkyl, with the proviso that
(1) R4 is attached to 2- or 3-position and
(2) when R4 is attached to 3-position, A4 is a bond or methylene, A3 is CH and Cyc1 is benzene, A1 is methylene, ethylnene or vinylene.), a non-toxic acid thereof or a hydrate thereof and
3) a method for the preparation of a compound of formula (I).
Unless otherwise specified, all isomers are included in the present invention. For example, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylene, alkenylene and alkynylene include straight-chain and branched-chain ones. Moreover, the isomers in the structure of double bond, ring, fused ring (E, Z, cis, trans), the isomers generated by the presence of asymmetric carbon atom(s) etc. (R, S isomers, xcex1, xcex2 isomers, enantiomers, diastereomers) optically active isomers having optical rotation (D, L, d, l isomers), isomers separated by chromatography (more polar or less polar isomers), equilibrium compounds, compounds of arbitrary ratio of these compounds.
In the present invention, C1xcx9c4 alkyl is methyl, ethyl, propyl, butyl and isomers thereof.
C1xcx9c8 alkyl is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
C1xcx9c4 alkoxy is methoxy, ethoxy, propoxy, butoxy and isomers thereof.
C1xcx9c4 alkylthio is methylthio, ethylthio, propylthio, butylthio and isomers thereof.
C1xcx9c4 alkylene is methylene, ethylene, trimethylene, tetramethylene and isomers thereof.
C2xcx9c4 alkenylene is ethenylene, propenylene, butenylene and isomers thereof.
Halogen is iodine, bromine, fluorine and chlorine.
Trihalomethyl is methyl group which is tri-substituted by iodine, bromine, fluorine or chlorine.
Trihalomethoxy is methoxy group which is tri-substituted by iodine, bromine, fluorine or chlorine.
Trihalomethylthio is methylthio group which is tri-substituted by iodine, bromine, fluorine or chlorine.
Carbocyclic ring represents C3xcx9c15 mono-, bi-, or tri-cyclic carbon ring and bridged carbocyclic ring. C3xcx9c15 mono-, bi-, or tri-cyclic carbon ring and bridged carbocyclic ring contains, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, pentalene, indene, naphthalene, azulene, fluorene, phenanthrene, anthracene, acenaphthylene, biphenylene, perhydronaphthalene, indane (dihydroindene), perhydroindene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, perhydroazulene, perhydrofluorene, perhydrophenanthrene, perhydroanthracene, perhydroacenaphthylene, perhydrophenylene, bicyclopentane, bicyclohexane, bicycloheptane ([2.2.1]bicycloheptane), bicyclooctane, bicyclononane, bicyclodecane, adamantane, etc.
Hetero ring includes a 4xcx9c18 membered mono-, di- or tri-cyclic hetero aryl, or partially or completely saturated one containing 1xcx9c4 of nitrogen, 1xcx9c2 of oxygen and/or 1 of sulfur.
Said 4xcx9c18 membered mono-, di- or tri-cyclic hetero aryl containing 1xcx9c4 of nitrogen, 1xcx9c2 of oxygen and/or 1 of sulfur includes pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, oxazepin, thiophene, thiain (thiopyran), thiepin, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, oxazine, ozadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzoimidazole, carbazole, acridine, etc.
Said 4xcx9c18 membered mono-, di- or tri-cyclic hetero aryl or partially or completely saturated one containing 1xcx9c4 of nitrogen, 1xcx9c2 of oxygen and/or 1 of sulfur includes pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, dihydropyridine, dihydropyrazine, dihydropyrimidine, dihydropyridazine, piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiaine (dihydrothiopyran), tetrahydrothiaine (tetrahydrothiopyran), dihydroxazole, tetrahydroxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, morpholine, thiomorpholine, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine, benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzazepine, benzodiazepine, indoloxazepine, indolotetrahydroxazepine, indoloxadiazepine, indolotetrahydroxadiazepine, indolothiazepine, indolotetrahydrothiazepine, indolothiadiazepine, indolotetrahydrothiadiazepine, indolazepine, indolotetrahydroazepine, indolodiazepine, indolotetrahydrodiazepine, benzofurazane, benzothiadiazole, benzotriazole, camphor, imidazothiazole, dihydrocarbazole, tetrahydrocarbazole, perhydrocarbazole, dihydroacridine, tetrahydroacridine, perhydroacridine, 1,3-dioxaindane, 1,4-dioxaindane ring, etc.
In the formula (I), R2 is preferably C1xcx9c4 alkyl, more preferably methyl and ethyl.
In the formula (I), Cyc1 is preferably, 
(wherein the bond in the right hand is attached to A1), more preferably 
(wherein the bond in the right hand is attached to A1.).
In the formula (I), A1 is preferably C1xcx9c4 alkylene, more preferably C1xcx9c2 alkylene (xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94).
In the formula (I), A2 is preferably xe2x80x94Oxe2x80x94.
In the formula (I), A3 is preferably CH.
In the formula (I), R4 is preferably attached to 3-position.
In the formula (I), R4 is preferably 
In the formula (I), A4 is preferably a bond, xe2x80x94C1xcx9c4 alkylene-Oxe2x80x94 or xe2x80x94C1xcx9c4 alkylene-Sxe2x80x94, more preferably a bond or xe2x80x94CH2xe2x80x94Sxe2x80x94. In the formula (I), R8 and R9 are preferably hydrogen or methyl, more preferably hydrogen.
In the formula (I), R1 is preferably hydrogen, C1xcx9c8alkyl, halogen, trihalomethoxy or trihalomethylthio, more preferably hydrogen, halogen or trihalomethoxy.
In the formula (I), a carbocyclic ring represented by Cyc2 is, preferably C3xcx9c10 mono- or bi-cyclic carbon ring, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane or benzene, particularly preferably, cyclopropane, cyclopentane, cyclohexane or benzene.
In the formula (I), a hetero ring represented by Cyc2 is preferably 3xcx9c10 membered mono- or bi-cyclic hetero aryl containing 1xcx9c2 of nitrogen, 1xcx9c2 of oxygen and/or 1 of sulfur or partly or totally saturated one, more preferably furan, thiophene, pyridine, quinoline, thiadiazole (1,2,3-thiadiazole), piperazine or dioxaindane (1,3-dioxaindane), particularly preferably dioxaindane (1,3-dioxaindane).
In the formula (I), a carbocyclic ring represented by R1 is preferably C3xcx9c10 mono- or bi-cyclic carbon ring, more preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane or benzene, particularly preferably cyclopropane, cyclopentane, cyclohexane or benzene.
In the formula (I), a hetero ring represented by R1 is preferably a 5xcx9c10 membered mono- or bi-cyclic hetero aryl or partially or completely saturated one containing 1xcx9c2 of nitrogen, 1xcx9c2 of oxygen and/or 1 of sulfur, more preferably furan, thiophene, pyridine, thiadiazole (1,2,3-thiazole), piperazine or dioxaindane (1,3-dioxaindane), particularly preferably thiadiazole (1,2,3-thiadiazole).
In the present invention, PPAR regulator includes all the regulators of PPAR xcex1, xcex3, xcex4, xcex1+xcex3, xcex1+xcex4, xcex3+xcex4 and xcex1+xcex3+xcex4. Preferable regulatory fashion is, PPAR xcex1 regulator, PPAR xcex4 regulator, PPAR xcex1+xcex3 regulator, PPAR xcex1+xcex4 regulator, more preferably PPAR xcex1+xcex3 regulator or PPAR xcex4 regulator.
PPAR regulator also includes PPAR agonist and PPAR antagonist, preferably PPAR agonist, more preferably PPAR xcex1 agonist, PPAR xcex4 agonist, PPAR xcex1+xcex3 agonist or PPAR xcex1+xcex3 agonist or PPAR xcex1+xcex4 agonist, particularly preferably PPAR xcex1+xcex3 agonist or PPAR xcex4 agonist.
Among the..compounds of formula (I), preferable ones are, a compound of formula (I-a) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-b) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-c) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-d) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-e) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-f) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-g) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-h) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-j) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-k) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-l) 
(wherein all symbols are as hereinbefore described), a compound of formula (I-m) 
a non-toxic salt thereof and a hydrate thereof.
Concrete compounds include the ones described in the following tables 1-20, non-toxic salts thereof and hydrates thereof.
In the following tables, Me represents methyl, Et represents ethyl, t-Bu represents t-butyl and the other symbols are as hereinbefore described.
(1) Among the compounds of the present invention of formula (I), the compounds wherein R4is 
i.e. the compounds of formula (I-1) 
(wherein R1-1 and COOR7-1 are the same meanings as R1 and COOR7 respectively, with the proviso that amino group represented by R1-1 is protected if necessary, COOH group represented by COOR7-1 is protected if necessary.
Protective groups for amino include, for example, benzyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl, etc., protective groups for COOH include, for example, methyl, ethyl, t-butyl, benzyl, etc. The other symbols are as hereinbefore described) may be prepared by subjecting to a reaction a compound of formula (II) 
(wherein all symbols are as hereinbefore described) and a compound of formula (III) 
(wherein all symbols are as hereinbefore described) or subjecting to a reaction a compound of formula (IV) 
(wherein R10 is halogen or methanesulfonyloxy and the other symbols are as hereinbefore described) and a compound of formula (V) 
(wherein R11 is hydroxy or mercapto and the other symbols are as hereinbefore described).
The reaction of a compound of formula (II) and a compound of formula (III) is known, for example, it is carried out in an organic solvent (dichloromethane, ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presence of azo compound (azodicarboxylic acid diethyl, azodicarboxylic acid diisopropyl, 1,1xe2x80x2-(azodicarbonyl)dipiperidine, 1,1xe2x80x2-azobis(N,N-dimethylformamide), etc.) and phosphine compound (triphenylphosphine, tributylphosphine, trimethylphosphine, etc.) at a temperature of from 0xc2x0 C. to 60xc2x0 C. for 3xcx9c20 hours.
The reaction of a compound of formula (IV) and a compound of formula (V) is known, for example, it is carried out in an inert organic solvent (tetrahydrofuran (THF), diethyl ether, dichloromethane, chloroform, carbon tetrachloride, pentane, hexane, benzene, toluene, dimethylformamide (DMF), dimethylsulfoxide (DMSO), hexamethylphosphoramide (HMPA), etc.) in the presence of base (sodium hydride, potassium carbonate, triethylamine, pyridine, cesium carbonate, etc.), optionally using an additive (sodium iodide, potassium iodide, etc.) at a temperature of from 0xc2x0 C. to 80xc2x0 C.
(2) Among the compounds of formula (I), the compounds wherein R4 is 2,4-thiazolidindion-5-yl, i.e. the compounds of formula (I-2) 
(wherein all symbols are as hereinbefore described) may be prepared by subjecting to a reaction a compound of formula (VI) 
(wherein X is halogen and the other symbols are as hereinbefore described) and thiourea.
The above reaction is known, for example, it is carried out in an organic solvent (methanol, ethanol, propanol, etc.) subjecting to a reaction a compound of formula (VI) and thiourea at a temperature of from 0xc2x0 C. to refluxing temperature for 3xcx9c20 hours, followed by addition of acid (concentrated sulfuric acid etc.) and then subjecting to a reaction at a temperature of 0xc2x0 C. to refluxing temperature for another 3xcx9c20 hours.
(3) Among the compounds of formula (I), the compounds wherein at least one of R1 and COOR7 is COOH or amino, i.e. the compounds of formula (I-3) 
(wherein R1-2 and COOR7-2 are the same meanings as R1 and COOR7, with the proviso that at least one of R1-2 and COOR7-2 is amino or COOH and the other symbols are as hereinbefore described) may be prepared by subjecting a compound of formula (I-1) to alkali hydrolysis, deprotection reaction under acidic conditions or deprotection reaction by hydration.
Deprotection reaction by alkali hydrolysis is known, for example, it is carried out in an organic solvent (methanol, ethanol, tetrahydrofuran, dioxane, etc.) using hydroxide of alkali metal (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), hydroxide of alkaline earth metal (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.) or an aqueous solution thereof or a mixture thereof at a temperature of from 0xc2x0 C. to 40xc2x0 C.
Deprotection reaction under acidic conditions is known, for example, it is carried out in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, anisole, etc.), in organic acid (acetic acid, trifluoroacetic acid, methanesulfonic acid, trimethylsilyl iodide etc.) or inorganic acid (hydrochloric acid, sulfuric acid, etc.) or a mixture thereof (hydrobromic acid-acetic acid etc.) at a temperature of from 0xc2x0 C. to 100xc2x0 C.
Deprotection reaction by hydration is known, for example, it is carried out in an inert solvent [ether (e.g. tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol (e.g. methanol, ethanol, etc.), benzene (e.g. benzene, toluene, etc.), ketone (e.g. acetone, methylethylketone, etc.), nitrile (e.g. acetonitrile etc.), amide (e.g. dimethylformamide etc.), water, ethyl acetate, acetic acid or a mixture of two or more thereof], in the presence of hydrating catalyst (e.g. palladium-carbon, palladium black, palladium, palladium hydroxide, platinum hydroxide, platinum dioxide, nickel, Raney-nickel, ruthenium chloride, etc.) in the presence or absence of inorganic acid (e.g. hydrochloric acid, sulfuric acid, hypochlorous acid, boronic acid, tetrafluoroboronic acid, etc.) or organic acid (e.g. acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid etc.), under normal atmosphere or suppressed atmosphere of hydrogen or in the presence of ammonium formate, at a temperature of from 0xc2x0 C. to 200xc2x0 C. In use of acid, its salt may be used.
(4) Among the compounds of formula (I), the compounds wherein R4 is 2,4-thiazolidinedion-5-yl and at least one of R1 is amino, i.e. the compounds of formula (I-4) 
(wherein R1-3 is the same meaning as R1, with the proviso that at least one of R1-3 is amino, and the other symbols are the same meaning as hereinbefore described) may be prepared by subjecting the said compound of formula (I-2) to deprotection reaction under acidic conditions or deprotection reaction by hydration.
Deprotection reaction under acidic conditions or deprotection reaction by hydration is carried out by the same procedure as hereinbefore described.
In the present invention deprotection reaction means a comprehensive deprotection reaction easily understood by those skilled in the art, for example, alkali hydrolysis, deprotection reaction under acidic condition, deprotection reaction by hydration. The desired compounds of the present invention can be easily prepared by these reactions.
As should be easily understood by those skilled in the art, methyl, ethyl, t-butyl and benzyl are included in the protective groups for carboxyl, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991 may be used.
Benzyloxycarbonyl, t-butoxycarbonyl and trifluoroacetyl are included in the protective groups for amino, but other groups that can be easily and selectively eliminated may also be used instead. For example, the groups described in T. W. Greene, Protective Groups in Organic Synthesis, Wiley, N.Y., 1991 may be used.
The compounds of formula (II), (III), (IV), (V) and (VI) are known per se or may be easily prepared by known methods.
For example, among the compounds of formula (II), 2-(5-methyl-2-phenyloxazol-4-yl)ethanol can be prepared by the method described in J. Med. Chem., 41, 5037-5054 (1998).
For example, the compounds of formula (IV), (V) and (VI) may be prepared by the method described in the following reaction schemes.
The symbols in the reaction schemes represent the followings and the other symbols are as hereinbefore described.
R11-1: protected hydroxy or mercapto;
A4-1: a bond or C1xcx9c4 alkylene;
A4-2: xe2x80x94C1xcx9c4 alkylene-Oxe2x80x94 or xe2x80x94C1xcx9c4 alkylene-Sxe2x80x94;
TMSCN: trimethylsilylcyanide;
Ph3P: triphenylphosphine;
ADDP: 1,1xe2x80x2-(azodicarbonyl)dipiperidine. 
The starting materials in the reaction schemes are known per se or may be prepared by known methods.
The reactions of the reaction schemes may be carried out by known methods.
The other starting materials and reagents in the present invention are known per se or may be prepared by known methods.
In each reaction described in the present specification, reaction products may be purified by conventional techniques. For example, purification may be carried out by distillation at atmospheric or reduced pressure, by high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, by washing or by recrystallization, etc. Purification may be carried out after each reaction, or after a series of reactions.
The compounds described in the present specification may be converted to corresponding salts by known methods. Non-toxic and water-soluble salts are preferable. Suitable salts include a salt of alkali metal (potassium, sodium, etc.), a salt of alkali earth metal (calcium, magnesium, etc.), an ammonium salt, a pharmaceutically acceptable salt of organic amine (tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, lysine, arginine, N-methyl-D-glucamine, etc.)
The compounds of formula (I) may be converted to corresponding acid addition salts by known methods. Non-toxic and water-soluble acid addition salts are preferable. Suitable acid addition salts include salts of inorganic acid (e.g. salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid) and salts of organic acid (e.g. salts of acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid,, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid), etc.
The compounds of the present invention described in the present specification or salts thereof may be converted to hydrates by a known method.
It was confirmed that a compound of the present invention of formula (I) has PPAR regulating activities by the following experiments.
1) Preparation of Materials Using Human PPAR xcex1, xcex3 or xcex4 in Luciferase Assay
The whole operation was based on basic gene engineering techniques, and in the operation conventional methods in yeast One-hybrid or Two-hybrid system were used.
As a luciferase gene expression vector under the control of thymidine kinase (TK) promotor, luciferase structural gene was excised from PicaGene Basic Vector 2 (A Brand Name, Toyo Ink Inc., catalogue No. 309-04821), to prepare luciferase gene expression vector pTK-Luc. under the control of TK promotor (xe2x88x92105/+51) as a minimum essential promotor activity from pTKxcex2 having TK promotor (Chrontech Inc., catalogue No.6179-9). In the upper stream of TK promotor, four times repeated UAS sequence was inserted, which is the response element of Ga14 protein, a basic transcription factor in yeast, to construct 4xc3x97UAS-TK-Luc. as reporter gene. The following is the enhancer sequence used (Sequence No. 1).
Sequence No. 1: Enhancer sequence repeating Ga14 response element four-times tandemly
5xe2x80x2-T(CGACGGAGTACTGTCCTCCG)xc3x974 AGCT-3xe2x80x2
A vector was prepared as described hereafter which expresses chimeric receptor protein wherein in carboxyl terminus of yeast Ga14 protein DNA binding domain was fused to ligand binding domain of human PPAR xcex1, xcex3 or xcex4. That is to say, PicaGene Basic Vector 2 (a Brand Name; Toyo Ink Inc., catalogue No. 309-04821) was used as a basic expression vector, the structural gene was exchanged for that of chimeric receptor protein, while promotor and enhancer domains were kept as they were.
DNA encoding a fused protein composed of Ga14 DNA binding domain, amino acids 1-147 linked to the ligand binding domain of human PPAR xcex1, xcex3 or xcex4 in frame was inserted to the downstream of promotor/enhancer in PicaGene Basic Vector 2 (a Brand Name). Here the DNA was aligned as follows; in the amino terminus of human PPAR xcex1, xcex3 or xcex4 ligand binding domain, nuclear translocation signal originated from SV-40 T-antigen, Ala Pro Lys Lys Lys Arg Lys Val Gly (sequence No. 2) was added to make fusion protein localizing intranuclearly. On the other hand, in the carboxy terminus of them, influenza hemagglutinin epitope, Tyr Pro Tyr Asp Val Pro Asp Tyr Ala (sequence No. 3) and stop codon for translation was added in this order, to detect an expressed fused protein tagged epitope sequence.
The portion of structural gene used as ligand binding domain of human PPAR xcex1, xcex3 or xcex4 is as follows: human PPAR xcex1 ligand binding domain: Ser167-Tyr468 human PPAR xcex3 ligand binding domain: Ser176-Tyr478 human PPAR xcex4 ligand binding domain: Ser139-Tyr441 in comparison with human PPAR xcex3 1 and human PPAR xcex3 2, Ser204-Tyr506 in human xcex3 2 is corresponding and identical to Ser176-Tyr478 in human PPAR xcex3 1), according to the comparison of human PPAR structures described in the literatures by R. Mukherjee at al. (See J. Steroid Biochem. Molec. Biol., 51, 157 (1994)), M. E. Green et al., (See Gene Expression., 4, 281 (1995)), A. Elbrecht et al. (See Biochem Biophys. Res. Commun., 224, 431 (1996)) or A. Schmidt et al. (See Mol. Endocrinology., 6, 1634 (1992)). In order to measure basal level of transcription, an expression vector containing DNA binding domain of Gal4 protein lacking in PPAR ligand binding domain, which is exclusively encoding the amino acids of No. 1xcx9cNo. 147 in Gal4 protein was also prepared.
2) Luciferase Assay Using Human PPAR xcex1, xcex3 or xcex4
CV-1 cells used as host cells were cultured by a conventional technique. That is to say, Dulbecco""s modified Eagle medium (DMEM) supplemented 10% bovine fetal serum (GIBCO BRL Inc., catalogue No. 26140-061) and 50 U/ml of penicillin G and 50 xcexcg/ml of streptomycin sulfate were used to culture CV-1 cells under the atmosphere of 5% carbon dioxide gas at 37xc2x0 C.
2xc3x97106 cells were seeded in a 10 cm dish, and once washed with the medium without serum, followed by addition of the medium (10 ml) thereto. Reporter gene (10 xcexcg), Gal4-PPAR expression vector (0.5 xcexcg) and 50 xcexcl of LipofectAMINE (a Brand Name, GIBRO BRL Inc., catalogue No. 18324-012) were well mixed and added to the culture to introduce these DNAs into the cells. They were cultured at 37xc2x0 C. for 5-6 hours, and thereto was added 10 ml of medium containing 20% of dialyzed bovine fetal serum (GIBRO BRL Inc., catalogue No. 26300-061), and then cultured at 37xc2x0 C. overnight. The cells were dispersed by trypsin, and they were again seeded in 96-well plates in a density of 8000 cells/100 xcexcl of DMEM-10% dialyzed serum/well. Several hours after the cultivation, cells were attached to the plastic ware, then 100 xcexcl of DMEM-10% dialyzed serum containing the compounds of the present invention, whose concentration is twice as high as the final concentration of them. The culture was settled at 37xc2x0 C. for 42 hours and the cells were dissolved, to measure luciferase activity according to manufacturer""s instruction.
As to PPAR xcex1 agonist activity, the relative activity of the compounds of the present invention (0.3 xcexcM) was shown in table 21, under the condition that luciferase activity was defined as 1.0 when a positive control compound carbaprostacyclin made a final concentration of 10 xcexcM, which apparently activated PPAR xcex1 (See Eur. J. Biochem., 233, 242 (1996); Genes and Development., 10, 974 (1996)).
As to PPAR xcex3 agonist activity, the relative activity of the compounds of the present invention (1.0 xcexcM) was shown in table 22, under the condition that luciferase activity was defined as 1.0 when a positive control compound troglitazone made a final concentration of 10 xcexcM, which significantly activated PPAR xcex3 (See Cell., 83, 863 (1995); Endocrinology., 137, 4189 (1996) and J. Med. Chem., 39, 665 (1996)) and has already launched.
As to PPAR xcex4 agonist activity, the relative activity of the compounds of the present invention was shown in table 23, under the condition that luciferase activity was defined as 1.0 when solvent containing no compound was added.
Furthermore, the reproducibility was very good in each point examined in triplicate. And dose dependent activation of PPARs thereof was also confirmed.
Hypoglycemic and Hypolipidemic Effects in KKAy Mice
Male, 7-weeks old KKAy/Ta mice weighed from 35 to 40 g (seven mice per group) were pre-breaded for approximately one week and acclimatized for three days on milled diet. On the first day of the experiment (Day 0), mice were divided into some groups by weight, plasma glucose and triglyceride (TG) levels to minimize the differences among groups. From the next day for two days they were given compounds by food mixture containing 0.03% (w/w) of the compound of the present invention or by milled diet only. At 13:00 of the third day, blood samples were collected and glucose and TG were measured. These results are shown in table 24. Additionally, there was no significant difference in the food intake between control group (milled diet only) and compounds-treated group (milled diet containing 0.03% compounds).
Hypocholesterolemic and Hypolipidemic Effects in Normal Rats
Male, six-weeks old SD rats (seven rats per group) were left to take milled diet and water ad libitum and were acclimatized for 1 week.
At 9:00 on the first day of the experiment (Day 0) blood sampling was done from tail vein. The rats were divided into some groups by body weight, trigiyceride(TG), non-esterified fatty acid (NEFA), total cholesterol (TC) values to minimize differences of the parameters among the groups. At 17:00 of the day the compound of the present invention suspended in 0.5%,aqueous solution of carboxymethylcellulose (CMC) was orally administered at a dose of 10 mg/kg, and thereafter, with hypercholesterolemic food (5.5% peanut oil, 1.5% cholesterol and 0.5% cholic acid were mixed with milled CRF-1 diet, Charles River Inc.) was given to the rats.
At 9:00 of the next day, blood sampling was done from tail vein. The lipid values in blood (TG, NEFA and TC values) were measured. The results are shown in table 25.
There was no significant difference of the food intake between the control group (provided only 0.5% CMC) and the group treated with the compounds of the present invention.
The hypoglycemic or hypolipidemic effects observed in KKAy mice imply the possibility of preventives and/or remedies for diabetes and hyperlipidemia, etc. Cholesterol-lowering and free fatty acid-lowering effects observed in high cholesterol diet-fed rats imply that the compounds of the present invention are useful as preventives and/or remedies of atherosclerosis etc.
[Effect]
The compounds of formula (I), non-toxic salts thereof and hydrates thereof have PPAR regulating effect, and therefore are expected to be applied as hypoglycemic agents, hypolipidemic agents, preventives and/or remedies for diseases associated with metabolic disorders (diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipidemia, atherosclerosis, hypertension, circulatory diseases, overeating, coronary heart diseases, etc., HDL cholesterol-elevating agents, LDL cholesterol and/or VLDL cholesterol-lowering agents and agents for relieving risk factors of diabetes or syndrome X.
The compounds of formula (I), non-toxic salts thereof and hydrates thereof have particularly PPAR xcex1 agonist and/or PPAR xcex3 agonist effect, and therefore are thought to be useful as hypoglycemic agents, hypolipidemic agents, preventives and/or remedies for diseases associated with metabolic disorders (diabetes, obesity, syndrome X, hypercholesterolemia, hyperlipoproteinemia, etc.), hyperlipidemia, atherosclerosis, hypertension, circulatory diseases, overeating, etc. coronary heart diseases, etc. Since they are expected to have HDL cholesterol-elevating effect, LDL cholesterol and/or VLDL cholesterol-lowering effect, inhibition of progress of atherosclerosis and its treatment, and inhibitory effect against obesity, they are also expected to be useful for the treatment and/or prevention of diabetes as hypoglycemic agents, for the amelioration of hypertension, for the relief from risk factors of syndrome X, and as preventives against occurrence of coronary heart diseases.
Since the compounds of formula (I), non-toxic salts thereof and hydrates thereof also have PPAR xcex4 agonist activity, they are expected to have HDL cholesterol-elevating effect, and therefore, they are expected to be useful as agents for the inhibition of progress of atherosclerosis and its treatment, hypolipidemic agents and/or hypoglycemic agents. Furthermore, they are also expected to be useful for the treatment of hyperglycemia, as hypoglycemic agents, for the treatment of diabetes, for the relief from risk factors of syndrome X, and as preventives against occurrence of coronary heart diseases.
[Toxicity]
The toxicity of the compounds of the present invention are very low and the compounds are safe enough for pharmaceutical use.
[Application to Pharmaceuticals]
For the purpose above described, the compounds of the present invention of formula (I), non-toxic salts, acid addition salts or hydrates thereof may normally be administered usually systemically or topically, orally or parenterally.
The doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment. In the human adult, the doses per person are generally in the range of from 1 mg to 1000 mg, by oral administration, up to several times per day, and in the range of from 0.1 mg to 100 mg, by parenteral administration (preferably intravenous administration), up to several times per day, or continuous administration from 1 to 24 hours per day from vein.
As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
The compounds of the present invention may be administered in the form of, for example, solid forms for oral administration, liquid forms for oral administration, injections, liniments or suppositories for parenteral administration.
Solid forms for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules, etc. Capsules include hard capsules and soft capsules.
In these solid forms, one or more of the active compound(s) may be admixed with excipients (e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch), binders (e.g. hydroxypropyl cellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate), disintegrants (e.g. cellulose calcium glycolate), lubricants (e.g. magnesium stearate), stabilizing agents, and adjuvants to assist dissolution (e.g. glutamic acid, aspartic acid) and prepared according to methods well known to those skilled in the art. The solid forms may, if desired, be coated with coating agents (e.g. sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
Liquid forms for oral administration include pharmaceutically acceptable aqueous solutions, suspensions and emulsions, syrups and elixirs, etc. In such forms, one or more of the active compound(s) may be dissolved, suspended or emulsified into diluent(s) commonly used in the art (e.g. purified water, ethanol or a mixture thereof). Besides such liquid forms may also comprise wetting agents, suspending agents, emulsifying agents, sweetening agents, flavoring agents, aroma, preservative or buffering agent, etc.
Injections for parenteral administration include sterile aqueous, suspensions, emulsions and solid forms which are dissolved or suspended into solvent(s) for injection immediately before use. In injections, one or more of the active compound(s) may be dissolved, suspended or emulsified into solvent(s). The solvents may include distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof.
Injections may comprise some additives, such as stabilizing agents, solution adjuvants (e.g. glutamic acid, aspartic acid or POLYSORBATE80 (registered trademark)), suspending agents, emulsifying agents, soothing agent, buffering agents, preservatives. They may be sterilized at the final step, or may be prepared and compensated according to sterile methods. They may also be manufactured in the form of sterile solid forms, which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before use.
Other forms for parenteral administration include liquids for external use, ointments and endermic liniments, inhalations, sprays, suppositories and pessaries for vaginal administration which comprise one or more of the active compound(s) and may be prepared by methods known per se. Sprays may comprise additional substances other than diluents, such as stabilizing agents (e.g. sodium sulfate), isotonic buffers (e.g. sodium chloride, sodium citrate or citric acid). For preparation of such sprays, for example, the method described in the U.S. Pat. No. 2,868,691 or 3,095,355 may be used.
The following Reference Examples and Examples illustrate the present invention, but do not limit the present invention.
The solvents in the parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations and TLC.
Solvents in the parentheses of NMR show the solvents used for measurement.